P1052: IMPACT OF SF3B1 MUTATION IN MYELOFIBROSIS
Authors: J. Senapati, S. Verstovsek, L. Masarova, N. Pemmaraju, G. Montalban Bravo, S. Pierce, L. Zhou, G. Garcia-Manero, H. Kantarjian, P. Bose
Journal: HemaSphere (2022)

Background: Splicing factor 3B subunit 1 (SF3B1) mutations have been shown to confer a unique phenotype in MDS and MDS/MPN overlap syndromes, with ring sideroblasts, thrombocytosis and a relatively favorable prognosis. In myelofibrosis (MF), the frequency of SF3B1 mutation is <10% and it may play a less important role in disease outcomes (Lasho et. al, Leukemia, 2011). Aims: We aimed to characterize the phenotypic and genotypic associations of SF3B1 mutations in pts with MF and compare them to SF3B1 wild type MF. Methods: We retrospectively analyzed all pts with WHO-defined MF (primary, including pre-fibrotic MF, or progressed from PV or ET) seen at our center from 1/2017 through 7/2021. All pts had a BM biopsy with karyotyping and most of the pts had an 81-gene myeloid mutation panel performed by next-generation sequencing (including JAK2, CALR, MPL and SF3B1) at presentation or at progression to MF from PV or ET. We compared the disease phenotypes, MPN driver and co-occurring mutations, cytogenetics, DIPSS, transfusion requirements, treatment characteristics and outcomes between pts with SF3B1 -mutated (SF3B1+) and -wild type (SF3B1-) MF. Results: 381 pts with MF were identified, 29 (8%) of whom were SF3B1+. There were similar frequencies of JAK2, CALR and MPL driver mutations and “triple negative” MF in the SF3B1+ and SF3B1- groups (Table 1). The median number of SF3B1 mutations was 1 (range, 1-2); K666N being the most common (52%), followed by K700E (14%). 10% SF3B1+ pts were DIPSS high risk, compared to 19% SF3B1- pts (p=0.3). There were no significant differences between the 2 groups in terms of baseline hemoglobin level, white blood cell count, platelets, co-occurring mutations, and symptom burden but more SF3B1+ pts were red blood cell (RBC)-transfusion dependent at presentation than SF3B1- pts (38% vs. 15%, p=0.003). A total of 152 (43%) SF3B1- pts and 14 (48%) SF3B1+ pts received ruxolitinib-based therapy (p=0.7). At a median follow up (mFU) of 17.2 months (mos) for the entire cohort (range, 0.1- 52.2 mos; mFU 22.6 mos for SF3B1+ and 16.8 mos for SF3B1-), 41 pts had died [4 (14%) SF3B1+ and 37(10%) SF3B1-] and 7 pts (1 SF3B1+ and 6 SF3B1-) had experienced leukemic transformation. The median estimated OS was 230 mos for SF3B1- vs. not reached for SF3B1+ pts (p = 0.57, Fig. 1). Table 1: - Patient chracteristics, treatment and outcomes Characteristics SF3B1+ (N= 29) SF3B1- (N= 352) p value N/Median (%) [range] Age, years 72 [54-91] 69 [21-89] Gender Males 24 (83) 202 (57) Diagnosis PMF 21 (72) 226 (64) Post ET/PV MF 8 (28) 126 (36) Baseline CBC Hb (g/dl) 9.7 [6.9-18.4] 10.5 [5.5-17.6] 0.4 WBC (109/L) 8.3 [1.3-73.3] 8.5 [1.1-212.1] 0.9 Platelet (109/L) 230 [19-1188] 216 [1-1271] 0.5 Driver mutation JAK2 18 (62) 214 (60) 0.9 CALR 5 (17) 82 (23) 0.6 MPL 3 (10) 29 (8) 0.7 Triple negative 3 (10) 32 (9) 0.7 JAK2 allele burden (n=28 SF3B1+,343 SF3B1-) 45 [1-81]% 47 [1-99]% 0.5 Co-mutations (n=20 SF3B1+, 205 SF3B1-) Splicing 3 (15) 59 (29) 0.3 Epigenetic 15 (75) 157 (76) 0.9 TP53 2 (10) 10 (5) 0.3 CTG (n=25 SF3B1+, 264 SF3B1-) Non diploid karyotype 12 (48) 102 (39) 0.4 BM fib (n=29 SF3B1+, 274 SF3B1-) Grade 3 3 (24) 113 (41) 0.001 DIPSS High 3 (10) 67 (19%) 0.3 Transfusion dependency RBC 11 (38) 52 (15) 0.003 Platelet 0 (0) 4 (1) 0.99 Events Leukemic transformation 1 (3) 6 (2) 0.4 Death 4 (14) 37 (10) Image:Summary/Conclusion:SF3B1 mutation is an uncommon event in MF and does not substantially affect the disease phenotype and outcomes. SF3B1 mutated MF pts appear to be more be RBC transfusion dependent given the underlying biology of SF3B1 mutation.